Extensive epidemiological evidence in humans and animal models suggests that poor maternal nutrition increases the susceptibility of the offspring to develop type-2 diabetes. Alterations in -cell development, leading to long-term defects in -cell mass and function is a major component of this phenotype. These observations identified the phenomena of fetal -cell programming. Although the importance of nutrition during -cell development as a risk for diabetes has been demonstrated, it is not entirely clear how nutrient signals regulate the differentiation program of the pancreas. The objective of this proposal is to determine the role of mTOR signaling on -cell development and programming by nutrient signals. The central hypothesis to be tested is that nutrient signals acting on mTOR modulate -cell development and susceptibility to diabetes by regulating pancreatic progenitor proliferation and survival. This will be tested by the following approach: Specific Aims 1 and 2 directly address how different nutrient signals acting through mTOR regulate proliferation and survival of pancreatic progenitors and -cell development. Aim 3 will identify the critical developmental window during which modulation of mTOR signaling regulates -cell programming and susceptibility to diabetes using inducible models with gain and loss of mTOR function. Long-term metabolic effects of transient inhibition of mTOR signaling during different stages of development will establish the critical window. Rescue of hyperglycemia in growth-retarded fetuses by transient activation of mTOR signaling during critical developmental period will also be performed. These studies will enhance our understanding of the molecular mechanisms that govern pancreas development and the long-term metabolic consequences of - cell programming by nutrient signals. This information can be used to design novel therapeutic approaches to improve -cell mass and function in diabetics and to modulate the differentiation program of pancreatic progenitors for therapeutic purposes. Finally, understanding the pathophysiology of glucose intolerance associated in individuals with intrauterine growth retardation is important for both prevention and therapy. PUBLIC HEALTH RELEVANCE: The mechanisms by which adverse intrauterine environment increases the susceptibility to develop glucose intolerance and type 2 diabetes are not well understood but a primary developmental insult to the -cell has been described. The goal of this application is to elucidate the mechanisms responsible for regulating pancreas development and -cell programming by nutrient signals in an effort to develop strategies to prevent diabetes in growth retarded fetuses and to identify pharmacological targets to improve -cell mass and function.